Effect of body mass index (BMI) and cigarette smoking on the pharmacokinetics of fentanyl

Pain is a common problem in cancer patients, occurring both in curative
settings as well as in palliative settings. Opioids are often used to treat
cancer pain. Fentanyl is one of the most widely used opioids.

Several preparations of fentanyl are currently available (1). The transdermal
fentanyl patch is developed for maintenance medication in chronic pain and is
the most commonly used form. Patches are available in different sizes,
consistent with specific delivery doses of these patches (12ug/hr, 25ug/hr,
50ug/hr, 75ug/hr or 100ug/hr). Fentanyl is absorbed through the intact skin
and a constant dose of drug is absorbed. Two different patches have been
developed; a reservoir patch and a matrix patch. These patches differ in the
way fentanyl is stored. However farmacokinetically, they are comparable (2, 3).
Nowadays, only the matrix patch is used in clinical practice.

After placement of the patch, the plasma fentanyl concentration gradually
increases. After 72hrs the patch has to be changed for a new one, as a stable
diffusion of the drug through the skin is no longer guaranteed. Steady state
concentrations are approached when a second transdermal fentanyl patch is
sticked on the skin (4). Removing the patch will not immediately lead to
diminished fentanyl concentrations because of the amount of fentanyl stored in
subcutaneous depots, and therefore systemic concentrations will gradually
decrease.

Fentanyl is a drug that is highly lipophilic and binds strongly to plasma
proteins. Fentanyl is more potent than morphine at equipotent dose levels (5).
The metabolism of fentanyl takes place primarily in the liver (6). Fentanyl is
mainly oxidized into the inactive metabolite norfentanyl by the CYP3A4
iso-enzyme (7). Less than 1% is metabolized to despropionyl-fentanyl,
hydroxyfentanyl, and hydroxynorfentanyl, which are also inactive metabolites.
Fentanyl is mainly excreted renally and for a minor part through the feces. The
large majority of the fentanyl is excreted as the metabolites mentioned; 10% as
unchanged drug (6).

Unfortunately there is a wide pharmacokinetic intra- and interpatient
variability in patients using a fentanyl patch. It is largely unclear which
factors contribute to this variability (8, 9). It is crucial to know which
factors influence fentanyl concentrations because of the risk of over- and
underdosing of fentanyl. An overdose of fentanyl could lead to serious
complications, including respiratory depression or ultimately death, while
underdosing fentanyl may lead to inadequate pain relief.

Fentanyl is dosed by titration. When pain is inadequately treated and side
effects are manageable the fentanyl dose is usually increased. Dose finding by
titration cannot be used in patients who switch from another opioid to
fentanyl. Usually these patients start with more or less the equi-analgetic
dose of fentanyl. Especially in these cases it would be extremely helpful if
could be predicted if these patients are at risk for under- or overdosing of
fentanyl.

Fentanyl is highly liphophilic and will be absorbed by the subcutaneous
fat-tissue. We hypothesize that higher fentanyl concentrations will be reached
when the patch is used by patients with thicker subcutaneous fat layers,
represented by patients with a higher body mass index (BMI). Most
farmacokinetic studies with fentanyl are performed in healthy volunteers or in
patients undergoing elective surgery. Unfortunately, not all studies reported
the BMI of the included patients. In studies with healthy volunteers BMI was
under 30kg/m2 (10, 11) or mean weight between 70 and 80 kg (3, 10, 12). Most
studies in patients undergoing surgery only included patients with a weight
under 100kg (13-16). Just a few studies have studied fentanyl farmacokinetics
in cancer patients. One of these studies showed significantly lower fentanyl
concentrations in cachectic patients (mean BMI 16 kg/m2) than in normal weigth
patients (mean BMI 23 kg/m2) using a fentanyl patch for 48 - 72hr (17). Two
other farmacokinetic studies in cancer patients did not show significant
differences between normal weight patients compared to cachectic patients (8,
9). However, in these studies patients in the lowest BMI group had a BMI <= 18.5
instead of a BMI of 16 in the study of Heiskanen (17).

Another factor that can be of influence on the pharmacokinetics of medication
is cigarette smoking. As 25% of the population in the Netherlands smokes
cigarettes, male vs female is 27% -23 %, probably a significant part of the
fentanyl users also are smokers (18).. .

The polycyclic aromatic hydrocarbons in cigarette smoke are believed to be
responsible
for the induction of cytochrome P450.(19, 20). A study with erlotinib showed a
significantly decreased AUC in smokers compared to nonsmokers (21). Both
erlotinib and fentanyl are mostly metabolized by CYP 3A4. A small part of the
metabolism of erlotinib is also influenced by CYP 1A1. Cigarette smoke induces
CYP 1A1 and can lead to a cascade, which also involves CYP 3A4, thereby
influencing the clearance of erlotinib (21). Probably, it also influences the
metabolism of fentanyl. A study from our group with irinotecan showed a lower
exposure to SN-38 (the active irinotecan metabolite) in smokers compared to
non-smokers. The hypothesis was that irinotecan is highly sensitive to CYP3A
induction and that this is modulated by cigarette smoking (22).. Possible
influence of smoking on clearance of fentanyl is important to know. Terminally
ill patients often change their habits in the last part of life. Heavy smokers
are physically not able to smoke as much as they did before, or occasional
smokers smoke more because of stress. Both scenarios can potentially influence
the fentanyl clearance. This may result in over- or underdosing of fentanyl,
causing intoxication or ineffective pain treatment.

As a result of these earlier publications, in this study we want to determine
which patient characteristics influence the pharmacokinetics of fentanyl.

Primary Objective:
to study the influence of a BMI < 20 or a BMI > 25 on the clearance of
fentanyl, in patients using a stable dose of the fentanyl patch (Durogesic ®).
to study the effects of smoking on the clearance of fentanyl, in patients using
a stable dose of the fentanyl patch (Durogesic ®).

Stable dose is defined as using the same dose of fentanyl during at least 8
days.

This is a multicenter pharmacokinetic cohort study. The trial will be performed
at the Erasmus MC Cancer Institute, department of Medical Oncology.

Patients with a stable dosage of fentanyl used through a patch can be included.
Stable dose is defined as at least 8 days using a stable fentanyl dosage. Blood
samples are always taken on the 2nd day of the used patch.

Patients will be asked to stick a fentanyl patch (Durogesic ®) during 3 periods
at the upper arm. During the third period, 1 venous blood sample will be
collected.

After taking the blood sample the patient has finished the study.

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